Intracerebral hemorrhage (ICH) is a common stroke with a high mortality. Even though patients survive the ictus, the resulting hematoma within brain parenchyma, triggers a series of events leading to secondary insults and severe neurological deficits. Hematoma absorption is a process of activated phagocytes to engulf and clean the hemorrhage and damaged tissue. Although phagocytosis is necessary to eliminate hematoma, release of pro-inflammatory mediators and free radicals during phagocyte activation is toxic to its neighbor cells, leading to secondary brain damage. How to promote phagocytosis timely and efficiently without harm to surrounding cells is important for recovery after ICH. Our study indicated that FDA approved clinical relevant PPAR? agonists, Rosiglitazone and Pioglitazone promoted hematoma resolution, decreased neuronal death, and improved functional recovery in a mice ICH model. Microglia isolated from murine brains showed more efficient phagocytosis in response to 15d-PGJ2 (a PPAR? ligand). PPAR? activators significantly increased expression of PPAR?-regulated genes (catalase and CD36), while it reduced neuronal damage and levels of proinflammatory genes and extracellular H2O2. Phagocytosis was significantly inhibited by PPAR? gene deletion and CD36 neutralizing antibody, while speeded-up by exogenous catalase. Our central hypothesis is that PPAR? activation within microglia/macrophages contributes to improved ICH outcome through augmenting phagocytosis/hematoma absorption, and by reducing inflammation-induced damage through mechanisms including: 1) transcriptional induction of CD36 and catalase expression and 2) inhibition of NF-?B activity and expression of NF-?B-regulated proinflammatory genes. We propose to use conditional macrophage/microglia PPAR?-knockout mice, adenovirus-mediated PPAR? gene deletion in primary microglia, CD36 and catalase deficient microglia and pharmacological tools to focus on the following 2 Specific Aims: 1) determine the role of microglia/macrophage PPAR? in the hematoma absorption, BBB disrupture and edema, and neurological functional recovery by using the conditional macrophage PPAR?-deficient animals; 2) explore the mechanism of PPAR? in microglia in promoting phagocytosis, inhibiting inflammatory response, and the effect of activated microglia on the survival of other brain cells by using the primary microglia/neuron co-cultures. Our long-term goal is to identify the molecular mechanism of PPAR? in phagocytosis/hematoma resolution and neuroprotection after ICH for future evaluation as a potential therapeutic target. [unreadable] [unreadable] [unreadable]